InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: SMAD4

Summary

InnateDB Protein

IDBP-3487.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

SMAD4

Protein Name

SMAD family member 4

Synonyms

DPC4; JIP; MADH4; MYHRS;

Species

Homo sapiens

Ensembl Protein

ENSP00000341551

InnateDB Gene

IDBG-3485 (SMAD4)

Protein Structure

UniProt Annotation

Function

In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000250, ECO:0000269PubMed:17327236, ECO:0000269PubMed:9389648}.

Subcellular Localization

Cytoplasm. Nucleus. Note=Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R- SMAD. PDPK1 prevents its nuclear translocation in response to TGF- beta.

Disease Associations

Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Note=The gene represented in this entry may be involved in disease pathogenesis.Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. {ECO:0000269PubMed:12417513, ECO:0000269PubMed:9811934}. Note=The disease is caused by mutations affecting the gene represented in this entry.Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth- factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown. {ECO:0000269PubMed:15031030}. Note=The disease is caused by mutations affecting the gene represented in this entry.Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry.Note=SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. {ECO:0000269PubMed:22158539, ECO:0000269PubMed:22243968}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 364 experimentally validated interaction(s) in this database.
They are also associated with 39 interaction(s) predicted by orthology.

Experimentally validated
Total	364 [view]
Protein-Protein	345 [view]
Protein-DNA	16 [view]
Protein-RNA	0
DNA-DNA	3 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	39 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000987	core promoter proximal region sequence-specific DNA binding
GO:0000988	protein binding transcription factor activity
GO:0001076	RNA polymerase II transcription factor binding transcription factor activity
GO:0001085	RNA polymerase II transcription factor binding
GO:0003677	DNA binding
GO:0003682	chromatin binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0005515	protein binding
GO:0005518	collagen binding
GO:0030616	transforming growth factor beta receptor, common-partner cytoplasmic mediator activity
GO:0042802	identical protein binding
GO:0042803	protein homodimerization activity
GO:0043565	sequence-specific DNA binding
GO:0044212	transcription regulatory region DNA binding
GO:0046872	metal ion binding
GO:0070411	I-SMAD binding
GO:0070412	R-SMAD binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0001658	branching involved in ureteric bud morphogenesis
GO:0001666	response to hypoxia
GO:0001701	in utero embryonic development
GO:0001702	gastrulation with mouth forming second
GO:0001822	kidney development
GO:0003190	atrioventricular valve formation
GO:0003198	epithelial to mesenchymal transition involved in endocardial cushion formation
GO:0003251	positive regulation of cell proliferation involved in heart valve morphogenesis
GO:0003279	cardiac septum development
GO:0003360	brainstem development
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006357	regulation of transcription from RNA polymerase II promoter
GO:0006366	transcription from RNA polymerase II promoter
GO:0006367	transcription initiation from RNA polymerase II promoter
GO:0007179	transforming growth factor beta receptor signaling pathway
GO:0007183	SMAD protein complex assembly
GO:0007369	gastrulation
GO:0007411	axon guidance
GO:0007492	endoderm development
GO:0007498	mesoderm development
GO:0008283	cell proliferation
GO:0008285	negative regulation of cell proliferation
GO:0009952	anterior/posterior pattern specification
GO:0010467	gene expression
GO:0010718	positive regulation of epithelial to mesenchymal transition
GO:0010862	positive regulation of pathway-restricted SMAD protein phosphorylation
GO:0014033	neural crest cell differentiation
GO:0017015	regulation of transforming growth factor beta receptor signaling pathway
GO:0030308	negative regulation of cell growth
GO:0030509	BMP signaling pathway
GO:0030511	positive regulation of transforming growth factor beta receptor signaling pathway
GO:0030513	positive regulation of BMP signaling pathway
GO:0032525	somite rostral/caudal axis specification
GO:0032909	regulation of transforming growth factor beta2 production
GO:0035556	intracellular signal transduction
GO:0036302	atrioventricular canal development
GO:0042118	endothelial cell activation
GO:0042127	regulation of cell proliferation
GO:0042177	negative regulation of protein catabolic process
GO:0045087	innate immune response (InnateDB)
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045893	positive regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048589	developmental growth
GO:0048663	neuron fate commitment
GO:0048729	tissue morphogenesis
GO:0048733	sebaceous gland development
GO:0048859	formation of anatomical boundary
GO:0051098	regulation of binding
GO:0051797	regulation of hair follicle development
GO:0060021	palate development
GO:0060391	positive regulation of SMAD protein import into nucleus
GO:0060395	SMAD protein signal transduction
GO:0060548	negative regulation of cell death
GO:0060956	endocardial cell differentiation
GO:0071559	response to transforming growth factor beta
GO:0072133	metanephric mesenchyme morphogenesis
GO:0072134	nephrogenic mesenchyme morphogenesis

Cellular Component

GO:0000790	nuclear chromatin
GO:0005622	intracellular
GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005667	transcription factor complex
GO:0005737	cytoplasm
GO:0005813	centrosome
GO:0005829	cytosol
GO:0032444	activin responsive factor complex
GO:0071141	SMAD protein complex